This invention relates to carboxylic acid derivatives, and associated pharmaceutically acceptable salts and solvates thereof, associated pharmaceutical compositions, and methods for use as prostaglandin IP (I2 or PGI2) antagonists.
Prostaglandins or prostanoids (PGs) are a group of bioactive compounds derived from membrane phospholipids and are formed from 20-carbon essential fatty acids containing three, four, or five double bonds, and a cyclopentane ring. They fall into several main classes designated by the letters D, E, F, G, H, or I, and they are distinguished by substitutions to the cyclopentane ring. The main classes are further subdivided by subscripts 1, 2, or 3, which reflect their fatty acid precursors. Thus, PGI2 has a double ring structure, and the subscript 2 indicates that it is related to arachidonic acid.
PGI2 (also known as prostacyclin) acts on platelets and blood vessels to inhibit aggregation and to cause vasodilation, and is thought to be important for vascular homeostasis. It has been suggested that PGI2 may contribute to the antithrombogenic properties of the intact vascular wall. PGI2 is also thought to be a physiological modulator of vascular tone that functions to oppose the actions of vasoconstrictors. The importance of these vascular actions is emphasized by the participation of PGI2 in the hypotension associated with septic shock. Although prostaglandins do not appear to have direct effects on vascular permeability, PGI2 markedly enhances edema formation and leukocyte infiltration by promoting blood flow in the inflamed region. Therefore, IP receptor antagonists may prevent conditions associated with excessive bleeding such as, but not limited to, hemophilia and hemorrhaging, may relieve hypotension related to septic shock, and may reduce edema formation.
Several in vivo analgesia studies in rodents suggest that PGI2 plays a major role in the induction of hyperalgesia. Likewise, in vitro studies provide substantial evidence to suggest that xe2x80x9cPGI2-preferringxe2x80x9d (IP) receptors act as important modulators of sensory neuron function (K. Bley et al, Trends in Pharmacological Sciences 1998, 19(4):141-147.). Since IP receptors in sensory neurons are coupled to activation of both adenylyl cyclase and phospholipase C, and hence, cAMP-dependent protein kinase and protein kinase C, these receptors can exert powerful effects on ion channel activity and thus neurotransmitter release. Evidence of a prominent role for IP receptors in inflammatory pain has been obtained from recent studies in transgenic mice lacking the IP receptor (T. Murata et al., Nature 1997, 388, 678-682).
In addition to being mediators of hyperalgesia, prostaglandins are known to be generated locally in the bladder in response to physiologic stimuli such as stretch of the detrusor smooth muscle, injuries of the vesical mucosa, and nerve stimulation (K. Anderson, Pharmacological Reviews 1993, 45(3), 253-308). PGI2 is the major prostaglandin released from the human bladder. There are some suggestions that prostaglandins may be the link between detrusor muscle stretch produced by bladder filling and activation of C-fiber afferents by bladder distension. It has been proposed that prostaglandins may be involved in the pathophysiology of bladder disorders. Therefore, antagonists of prostaglandin IP receptors are expected to be useful in the treatment of such conditions.
Antagonists of IP receptors are also expected to find a utility in respiratory allergies wherein PGI2 production in response to an allergen is present, or in respiratory conditions such as asthma.
Additional information relating to prostaglandins and their receptors is described in Goodman and Gillman""s, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, 1996, Chapter 26, pages 601-616. Thus antagonists which can selectively treat the above mentioned conditions by acting on the IP receptor, are desirable.
U.S. Pat. No. 5,250,517 assigned to F. Hoffmann-La Roche AG refers to certain N-hydroxyalkyl amino acid amide derivatives as inhibitors of renin for treating hypertension.
U.S. Pat. No. 5,610,176 and U.S. Pat. No. 5,981,755 assigned to Warner-Lambert refer to certain indole derivatives useful as tachykinin receptor antagonists.
EP published application EP 902018 assigned to F. Hoffmann-La Roche AG refers to certain 2-(arylphenyl)amino-imidazoline derivatives as IP antagonists.
PCT published application WO 97/19911 assigned to Thomae refers to certain amino acid derivatives as neuro-peptide Y antagonists.
Japanese patent applications JP 06184086 and JP 06072985 refer to certain tetrazolylbiphenylmethylurea derivatives as angiotensin II antagonists.
German patent application DE 1934783 assigned to Farbenfabrik Bayer AG and French patent application FR 1554051 assigned to Ciba Ltd refer to the use of biphenylisopropoxycarbonyl derivatives as amino protecting reagents in the synthesis of peptides.
Bley et al., Trends in Pharmacological Sciences 1998, 19 (4), 141-147 refer to the role of IP prostanoid receptors in inflammatory pain.
Smith et al., British Journal of Pharmacology 1998, 124(3), 513-523 refer to characterization of prostanoid receptor-evoked responses in rat sensory neurons.
Murata et al., Nature 1997, 388 (6643), 678-682 refer to altered pain perception and inflammatory response in mice lacking prostacyclin receptors.
Anderson et al., Pharmacological Reviews 1993, 45(3), 253-308 refer to Pharmacology of lower urinary tract smooth muscles and penile erectile tissues.
Coleman et al., Pharmacological Review 1994, 46(2), 205-229 refer to properties, distribution and structure of prostanoid receptors and their subtypes.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
This invention relates to compounds comprising Formula I: 
wherein:
R1, R2, and R3 are each independently in each occurrence optionally substituted aryl or optionally substituted heteroaryl;
R4 is xe2x80x94COOH or tetrazolyl;
A is independently in each occurrence a single bond, xe2x80x94O(CH2)pxe2x80x94, xe2x80x94S(CH2)pxe2x80x94, xe2x80x94NRxe2x80x2(CH2)pxe2x80x94, xe2x80x94(CH2)pOxe2x80x94, xe2x80x94O(CH2)pOxe2x80x94, xe2x80x94(CH2)pO(CH2)pxe2x80x94, xe2x80x94(CH2)nCO(CH2)nxe2x80x94, xe2x80x94CONxe2x80x94, xe2x80x94NCOxe2x80x94; xe2x80x94(CH2)pxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94;
Rxe2x80x2 is hydrogen or lower alkyl;
B is independently in each occurrence xe2x80x94(CH2)qxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94 or xe2x80x94CH2Nxe2x80x94;
m, p, and q are each independently in each occurrence an integer from 1 to 3 inclusive;
n and r are each independently in each occurrence an integer from 0 to 3 inclusive;
or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, R4 is xe2x80x94COOH.
In a preferred embodiment, R4 is xe2x80x94COOH, R1 and R2 are optionally substituted aryl; more preferably, R4 is xe2x80x94COOH, R1 and R2 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano; and even more preferably R4 is xe2x80x94COOH, R1 and R2 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and A is a single bond or xe2x80x94(CH2)pxe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 and R2 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R3 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, A is a single bond, m is 1, n and r are 0, and B is xe2x80x94CH2xe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 and R2 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and A is xe2x80x94(CH2)pOxe2x80x94, xe2x80x94O(CH2)pxe2x80x94, or xe2x80x94(CH2)pO(CH2)pxe2x80x94; in a more preferred embodiment, R4 is xe2x80x94COOH, R1, R2 and R3 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, A is xe2x80x94(CH2)pOxe2x80x94, xe2x80x94O(CH2)pxe2x80x94, or xe2x80x94(CH2)pO(CH2)pxe2x80x94, m is 1, n and r are 0, and B is xe2x80x94CH2xe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is optionally substituted heteroaryl, and R2 is optionally substituted aryl; more preferably, R4 is xe2x80x94COOH, R1 is optionally substituted heteroaryl, and R2 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano; and even more preferably, R4 is xe2x80x94COOH, R1 is optionally substituted heteroaryl, R2 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and A is a single bond.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is optionally substituted heteroaryl, R2 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and A is xe2x80x94(CH2)pOxe2x80x94 or xe2x80x94O(CH2)pxe2x80x94; more preferably, R4 is xe2x80x94COOH, R1 is optionally substituted indolyl, R2 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and A is xe2x80x94O(CH2)pxe2x80x94, m is 1, n and r are 0, and B is xe2x80x94CH2xe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 and R2 are optionally substituted heteroaryl; more preferably R4 is xe2x80x94COOH, R1 is optionally substituted heteroaryl, and R2 is independently in each occurrence indolyl, indazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, isoquinolinyl, or quinolinyl all optionally substituted; and even more preferably, R4 is xe2x80x94COOH, R1 is optionally substituted heteroaryl, R2 is independently in each occurrence indolyl, indazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, isoquinolinyl, or quinolinyl, all optionally substituted, and A is a single bond.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is optionally substituted heteroaryl, R2 is independently in each occurrence indolyl, indazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, isoquinolinyl, or quinolinyl, all optionally substituted, and A is xe2x80x94(CH2)pOxe2x80x94 or xe2x80x94O(CH2)pxe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is optionally substituted aryl, and R2 is optionally substituted heteroaryl; more preferably R4 is xe2x80x94COOH, R1 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, and R2 is independently in each occurrence indolyl, indazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, isoquinolinyl, or quinolinyl, all optionally substituted; and more preferably R4 is xe2x80x94COOH, R1 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is independently in each occurrence indolyl, indazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, isoquinolinyl, or quinolinyl, all optionally substituted, and A is a single bond or xe2x80x94(CH2)pxe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is independently in each occurrence indolyl, indazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, isoquinolinyl, or quinolinyl, all optionally substituted, and A is xe2x80x94(CH2)pOxe2x80x94 or xe2x80x94O(CH2)pxe2x80x94; more preferably R4 is xe2x80x94COOH, R1 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzofuranyl, and A is xe2x80x94(CH2)pOxe2x80x94 or xe2x80x94O(CH2)pxe2x80x94; even more preferably R4 is xe2x80x94COOH, R1 and R3 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzofuranyl, A is xe2x80x94(CH2)pOxe2x80x94 or xe2x80x94O(CH2)pxe2x80x94, m is 1, n and r are 0, and B is xe2x80x94CH2xe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzofuranyl, and A is a single bond or xe2x80x94(CH2)pxe2x80x94; more preferably R4 is xe2x80x94COOH, R1 and R3 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzofuranyl, and A is a single bond, m is 1, n and r are 0, and B is xe2x80x94CH2xe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzoxazolyl, and A is a single bond or xe2x80x94(CH2)pxe2x80x94; more preferably R1 and R3 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzoxazolyl, A is a single bond, m is 1, n and r are 0, and B is xe2x80x94CH2xe2x80x94.
In another preferred embodiment, R4 is xe2x80x94COOH, R1 is phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzoxazolyl, and A is xe2x80x94(CH2)pOxe2x80x94 or xe2x80x94O(CH2)pxe2x80x94; more preferably R4 is xe2x80x94COOH, R1 and R3 are phenyl optionally substituted with one or more substituents selected from lower alkyl, halo, hydroxyl, alkoxy, or cyano, R2 is optionally substituted benzoxazolyl, A is xe2x80x94(CH2)pOxe2x80x94 or xe2x80x94O(CH2)pxe2x80x94; m is 1, n and r are 0, and B is xe2x80x94CH2xe2x80x94.
In another preferred embodiment, the compound is 2-(biphenyl-4-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(4-phenethyloxy-benzyloxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(2-phenyl-benzofuran-5-ylmethoxycarbonylamino)-3-phenyl propionic acid; (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid; (R)-2-(5-phenyl-benzofuran-3-ylmethoxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(2-Fluoro-phenoxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid; 2-(3-fluoro-4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(3-fluoro-phenoxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; 2-(biphenyl-4-methoxycarbonyl)amino-3-(3-indolyl)propionic acid; 3-(3-benzenesulfonylamino-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; 3-(3-benzenesulfonylamino-phenyl)-2-(4-phenoxymethyl-benzyloxycarbonylamino)-propionic acid; 3-(3-benzenesulfonylamino-phenyl)-2-(biphenyl-4-ylmethoxycarbonylamino)-propionic acid; (S)-2-phenyl-2-(5-phenyl-1H-indol-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(4-chloro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(3-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(4-methoxy-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid;(R)-3-(4-fluoro-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(4-methyl-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-(2-benzyl-benzofuran-5-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-3-phenyl-2-(5-phenyl-benzoxazol-2-ylmethoxycarbonylamino) propionic acid; (R)-3-phenyl-2-(2-phenyl-benzoxazol-5-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(1H-indol-4-yl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; 2-[4-(1H-indol-4-ylmethoxy)-benzyloxycarbonylamino]-3-phenyl-propionic acid; 2-(4-benzyloxybenzylcarbonylamino)-3-phenyl-propionic acid; 2-[4-(1H-indol-5-ylmethoxy)-benzyloxycarbonylamino]-3-phenyl-propionic acid; (R)-2-(5-benzo[1,3]dioxol-5-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid (R)-2-[5-(3-cyano-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-3-phenyl-2-(5-phenyl-2,3-dihydro-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-3-(4-fluoro-phenyl)-2-(5-pyridin-3-yl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[2-(4-fluoro-phenyl)-benzoxazol-5-ylmethoxycarbonylamino]-3-phenyl-propionic acid (R)-2-[5-(3-cyano-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-[5-(3,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(2-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(2,3-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-3-(4-fluoro-phenyl)-2-[5-(2-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-2-[5-(2-chloro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-(5-benzo[1,3]dioxol-5-yl-benzofuran-2-ylmethoxycarbonylamino)-3-(4-fluoro-phenyl)-propionic acid; (R)-3-(4-chloro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-2-(5-benzo[1,3]dioxol-4-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-2-[2-(3-cyano-phenyl)-benzoxazol-5-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-3-(4-bromo-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-3-(4-chloro-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-3-(3-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-3-(3-fluoro-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(2,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(3,4-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(2,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-[5-(3,4-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-[5-(3,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-3-phenyl-2-(2-phenyl-quinolin-6-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(1H-indol-5-yl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[2-(1H-indol-4-yl)-benzoxazol-5-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[2-(3,5-difluoro-phenyl)-benzoxazol-5-ylmethoxycarbonylamino]-3-phenyl-propionic acid; 2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-pyridin-4-yl-propionic acid; and 2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-pyridin-3-yl-propionic acid; or an individual isomer, racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvate thereof.
Another aspect of the invention relates to pharmaceutical compositions suitable for administration to a subject, comprising as an ingredient a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one pharmaceutically acceptable carrier; more preferably the at least one compound is suitable for administration to a subject having a disease state which is alleviated by treatment with an IP receptor modulator, and in an even more preferably wherein the at least one compound is suitable for administration to a subject having a disease state which is alleviated by treatment with an IP receptor antagonist.
An additional aspect of the invention relates to methods of treatment comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one compound of Formula I or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, the invention further relates to methods of treatment comprising administering to a subject in need of such treatment, a therapeutically effective amount of a composition containing at least one compound of Formula I or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, the invention further relates to methods for treating a subject having a disease state that is alleviated by treatment with an IP receptor antagonist, which comprises administering to such a subject a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, the disease state is associated with the urinary tract, pain, inflammation, respiratory states, edema formation, or hypotensive vascular diseases that can be alleviated by treatment with an IP receptor antagonist.
In a preferred embodiment, the disease state is associated with the lower urinary tract; more preferably the disease state comprises bladder disorders associated with bladder outlet obstruction and urinary incontinence conditions such as bladder outlet obstruction, urinary incontinence, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiophatic bladder hypersensitivity.
In another preferred embodiment, the disease state is pain, more preferably the disease state comprises inflammatory pain, neuropathic pain, cancer pain, acute pain, chronic pain, surgical pain, dental pain, premenstrual pain, visceral pain, pain due to burns, migraine or cluster headaches, neuralgias, post traumatic injuries, pain associated with functional bowel disorders such as irritable bowel syndrome, hyperalgesia, or complex regional syndromes.
In another preferred embodiment, the disease state is inflammation; more preferably the disease state comprises inflammation from bacterial, fungal or viral infections, rheumatoid arthritis, osteoarthritis, surgery, bladder infection or idiopathic bladder inflammation, pelvic hypersensitivity, urethritis, prostatitis, prostatodynia or conjunctivitis.
In another embodiment, the disease state comprises respiratory states from allergies or asthma.
In another embodiment, the disease state comprises edema formation.
In another embodiment, the disease state comprises states associated with hypotensive vascular diseases, preferably the disease state comprises relief of hypotension associated with septic shock.
Another aspect of the invention relates to a process which comprises reacting a compound having a general formula
R1xe2x80x94Axe2x80x94R2xe2x80x94(CH2)mxe2x80x94OH 
with a compound of general formula 
followed by hydrolysis to provide a compound of the general formula 
wherein R5 is C1-4-alkyl, R4 is COOH, and R1, R2, R3, A, B, m, n, and r are as defined herein.
In yet another aspect, the invention relates to a process which comprises reacting a compound having a general formula
R1xe2x80x94Axe2x80x94R2xe2x80x94(CH2)mxe2x80x94OC(O)L 
wherein L is a leaving group,
with a compound of general formula 
followed by hydrolysis to provide a compound of the general formula 
wherein R5 is C1-4-alkyl, R4 is COOH, and R1, R2, R3, A, B, m, n, and r are as defined herein.
In yet another aspect, the invention relates to a process which comprises reacting a compound having a general formula 
with a compound of general formula 
followed by hydrolysis to provide a compound of the general formula 
wherein R5 is C1-4-alkyl, R4 is COOH, and R1, R2, R3, A, B, m, n, and r are as defined herein.
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise.
xe2x80x9cAlkylxe2x80x9d means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms inclusive, unless otherwise indicated. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
xe2x80x9cLower alkylxe2x80x9d means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms inclusive, unless otherwise indicated. Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means the divalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to six carbons inclusive, unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene, and the like.
xe2x80x9cAlkoxyxe2x80x9d means the radical xe2x80x94Oxe2x80x94R, wherein R is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means the radical Rxe2x80x94Oxe2x80x94C(O)xe2x80x94, wherein R is a lower alkyl radical as defined herein. Examples of alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, sec-butoxycarbonyl, and the like.
xe2x80x9cArylxe2x80x9d means the monovalent or divalent aromatic hydrocarbon radical consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with one or more, preferably one or two substituents selected independently from hydroxy, cyano, lower alkyl, lower alkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylcarbonylamino, arylcarbonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonylamino, or arylsulfonylamino and/or trifluoromethyl unless otherwise indicated. Alternatively two adjacent atoms of the aryl ring may be substituted with a methylenedioxy or ethylenedioxy group. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, 1,3,-benzodioxolyl, 3-benzenesulfonylamino-phenyl, 1-phenyl-methanoyl-amino-phenyl; acetylaminophenyl, 3-nitrophenyl, tert-butyl phenyl, indanyl, 4-fluoro-phenyl, anthraquinolyl, and the like.
xe2x80x9cArylalkylxe2x80x9d means the radical Rxe2x80x2Rxe2x80x3-, wherein Rxe2x80x2 is an aryl radical as defined herein, and Rxe2x80x3 is an alkyl radical as defined herein. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means the monovalent or divalent aromatic carbocyclic radical having one or more rings incorporating one, two, or three heteroatoms within the ring (chosen from nitrogen, oxygen, or sulfur) which can optionally be substituted with one or more substituents selected from preferably one or two substituents selected independently from hydroxy, cyano, lower alkyl, lower alkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylcarbonylamino, arylcarbonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonylamino, or arylsulfonylamino and/or trifluoromethyl unless otherwise indicated. Examples of heteroaryl radicals include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridazinyl, pyrazinyl, thiophenyl, furanyl, pyrimidinyl, pyridinyl, quinolin-2,6-diyl, quinolinyl, isoquinolinyl, 1,3-benzodioxole, benzofuranyl, benzofuran-2,5-diyl, benzofuran-3,5-diyl, 2,3-dihydrobenzofuran-2,5-diyl, benzothiophen-2,5-diyl, benzothiopyranyl, benzimidazol-2,5-diyl, benzoxazolyl-2,5-diyl, benzothiazolyl, benzopyranyl, indazolyl, indol-5-yl, indol-4-yl, indol-1-yl, indol-2,5-diyl, N-alkyl-indolyl, isoindolyl, quinolinyl, isoquinolinyl, naphtyridinyl, and the like.
xe2x80x9cHaloxe2x80x9d means the radical fluoro, bromo, chloro, and/or iodo.
xe2x80x9cAminoxe2x80x9d means the radical xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are hydrogen or a lower alkyl radical as defined herein. Examples of amino radicals include, but are not limited to xe2x80x94NH2, methylamino, diethylamino(1-ethylethyl)amino, and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d means the radical xe2x80x94SO2R, wherein R is a lower alkyl radical as defined herein. Examples of alkylsulfonyl radicals include, but are not limited to, methylsulfonyl, (1-ethylethyl)sulfonyl, and the like.
xe2x80x9cArylsulfonylxe2x80x9d means the radical xe2x80x94SO2R, wherein R is an aryl radical as defined herein. Examples of arylsulfonyl radicals include, but are not limited to, phenylsulfonyl, naphthylsulfonyl, and the like.
xe2x80x9cAlkylaminosulfonylxe2x80x9d means the radical xe2x80x94SO2NHR, wherein R is a lower alkyl radical as defined herein. Examples of alkylaminosulfonyl radicals include, but are not limited to, methylaminosulfonyl, ethylaminosulfonyl, and the like.
xe2x80x9cArylaminosulfonylxe2x80x9d means the radical xe2x80x94SO2NHR, wherein R is an aryl radical as defined herein. Examples of arylaminosulfonyl radicals include, but are not limited to, phenyl aminosulfonyl, naphthylaminosulfonyl, and the like.
xe2x80x9cAlkylsulfonylaminoxe2x80x9d means the radical xe2x80x94NHSO2R, wherein R is a lower alkyl radical as defined herein. Examples of alkylsulfonylamino radicals include, but are not limited to, methylsulfonylamino, propylsulfonylamino, and the like.
xe2x80x9cArylsulfonylaminoxe2x80x9d means the radical xe2x80x94NHSO2R, wherein R is an aryl radical as defined herein. Examples of arylsulfonylamino radicals include, but are not limited to, phenylsulfonylamino, naphthylsulfonylamino, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptional bondxe2x80x9d means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
xe2x80x9cLeaving groupxe2x80x9d means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions. Examples of leaving groups include, but are not limited to, halo, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
xe2x80x9cProtective groupxe2x80x9d or xe2x80x9cprotecting groupxe2x80x9d means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotective reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive oxygen atoms present in the reactants. Acceptable protective groups for alcoholic or phenolic hydroxyl groups, which may be removed successively and selectively includes groups protected as acetates, haloalkyl carbonates, benzyl ethers, alkylsilyl ethers, heterocyclyl ethers, and methyl or alkyl ethers, and the like. Protective or blocking groups for carboxyl groups are similar to those described for hydroxyl groups, preferably tert-butyl, benzyl or methyl esters.
xe2x80x9cInert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d means the solvent inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
xe2x80x9cIsomerismxe2x80x9d means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereoisomersxe2x80x9d, and stereoisomers that are non-superimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d.
xe2x80x9cChiral isomerxe2x80x9d means a compound with one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 51 1; Cahn et al. Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. (London) 1951, 612; Cahn et al. Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
xe2x80x9cGeometric Isomersxe2x80x9d means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
xe2x80x9cAtropic isomersxe2x80x9d means the isomers owing their existence to restricted rotation caused by hindrance of rotation of large groups about a central bond.
xe2x80x9cSubstantially purexe2x80x9d means at least about 90 mole percent, more preferably at least about 95 mole percent, and most preferably at least about 98 mole percent of the desired enantiomer or stereoisomer is present compared to other possible configurations.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, (4-hydroxybenzoyl)benzoic acid, camphorsulfonic acid, p-chlorobenzenesulfonic acid, cinnamic acid, citric acid, cylcopentanepropionic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, heptanoic acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), muconic acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenyl-propionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiary butylacetic acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, dicyclohexylamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, t-butylamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
The preferred pharmaceutically acceptable salts are the salts formed from sodium, potassium, lithium, t-butylamine, or dicyclohexylamine.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
xe2x80x9cCrystal formsxe2x80x9d (or polymorphs) means crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
xe2x80x9cSolvatesxe2x80x9d means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.
xe2x80x9cProdrugxe2x80x9d means a pharmacologically inactive form of a compound which must be metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. The prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific site. Although metabolism occurs for many compounds primarily in the liver, almost all other tissues and organs, especially the lung, are able to carry out varying degrees of metabolism. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve easy of formulation, or provide site-specific delivery of the compound. Reference to a compound herein includes prodrug forms of a compound.
xe2x80x9cSubjectxe2x80x9d means mammals and non-mammals. Mammals means any member of the Mammalia class including, but not limited to humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term xe2x80x9csubjectxe2x80x9d does not denote a particular age or sex.
xe2x80x9cTherapeutically effective amountxe2x80x9d means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, and disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. xe2x80x9cPharmacological effectxe2x80x9d as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. A pharmacological effect means that the indications of the subject being treated are prevented, alleviated, or reduced.
xe2x80x9cDisease statexe2x80x9d means any disease, condition, symptom, or indication.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease state includes:
(1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
(2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or
(3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
xe2x80x9cModulatorxe2x80x9d means a molecule, such as a compound, that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
xe2x80x9cAntagonistxe2x80x9d means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone, that diminishes or prevents the action of another molecule or receptor site.
xe2x80x9cTraumaxe2x80x9d means any wound or injury. Trauma can produce, for example, acute and/or chronic pain, inflammatory pain, and neuropathic pain.
xe2x80x9cPainxe2x80x9d means the more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. There are many types of pain, including, but not limited to, lightning pains, phantom pains, shooting pains, acute pain, inflammatory pain, neuropathic pain, complex regional pain, neuralgia, neuropathy, and the like (Dorland""s Illustrated Medical Dictionary, 28th Edition, W. B. Saunders Company, Philadelphia, Pa.). The goal of treatment of pain is to reduce the degree of severity of pain perceived by a treatment subject.
xe2x80x9cNeuropathic painxe2x80x9d means the pain resulting from functional disturbances and/or pathological changes as well as noninflammatory lesions in the peripheral nervous system. Examples of neuropathic pain include, but are not limited to, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, diabetic pain, entrapment pain, and the like.
xe2x80x9cHyperalgesiaxe2x80x9d means the pain that results from an excessive sensitiveness or sensitivity.
xe2x80x9cAllodyniaxe2x80x9d means the pain that results from a non-noxious stimulus to the skin. Examples of allodynia include, but are not limited to, cold allodynia, tactile allodynia, and the like.
xe2x80x9cComplex regional pain syndromesxe2x80x9d means the pain that includes, but is not limited to, reflex sympathetic dystrophy, causalgia, sympathetically maintained pain, and the like.
xe2x80x9cCausalgiaxe2x80x9d means the burning pain, often accompanied by trophic skin changes, due to injury of a peripheral nerve.
xe2x80x9cNociceptionxe2x80x9d means the pain sense. xe2x80x9cNociceptorxe2x80x9d means the structure that mediates nociception. Nociception may be the result of a physical stimulus, such as, mechanical, electrical, thermal, or a chemical stimulus. Most nociceptors are in either the skin or the viscera walls.
xe2x80x9cAnalgesiaxe2x80x9d means the relief of pain without the loss of consciousness. An xe2x80x9canalgesicxe2x80x9d is an agent or drug useful for relieving pain, again without the loss of consciousness.
xe2x80x9cDisorders of the urinary tractxe2x80x9d or xe2x80x9curopathyxe2x80x9d used interchangeably with xe2x80x9csymptoms of the urinary tractxe2x80x9d means the pathologic changes in the urinary tract. Examples of urinary tract disorders include, but are not limited to, bladder outlet obstruction, urinary incontinence, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiophatic bladder hypersensitivity, and the like.
xe2x80x9cOveractive bladderxe2x80x9d or xe2x80x9cDetrusor hyperactivityxe2x80x9d includes, but is not limited to, the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, and the like; and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like.
xe2x80x9cOutlet obstructionxe2x80x9d includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors and the like. It is usually symptomatically manifested as obstructive (low flow rates, difficulty in initiating urination, and the like), and irritative (urgency, suprapubic pain, and the like).
xe2x80x9cOutlet insufficiencyxe2x80x9d includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, or mixed incontinence. It is usually symptomatically manifested as stress incontinence.
xe2x80x9cPelvic Hypersensitivityxe2x80x9d includes but is not limited to pelvic pain, interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia, urethritis, orchidalgia, and the like. It is symptomatically manifested as pain, inflammation or discomfort referred to the pelvic region, and usually includes symptoms of overactive bladder.
Throughout the application the following abbreviations are used with the following meanings:
Nomenclature
In general, the nomenclature used in this Application is based on AUTONOM(trademark) v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature.
For example, a compound of Formula I wherein R1, R2, and R3 are phenyl, R4 is xe2x80x94COOH, A is xe2x80x94OCH2xe2x80x94, B is xe2x80x94CH2xe2x80x94, m and n are 1, and r is 0 is named 2-(4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid.
Preferred Compounds
Among compounds of the present invention set forth in the Summary of the Invention, certain compounds of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof are preferred.
R1 is independently in each occurrence preferably optionally substituted aryl or optionally substituted heteroaryl, and even more preferably optionally substituted phenyl or optionally substituted indolyl.
R2 is independently in each occurrence preferably optionally substituted aryl or optionally substituted heteroaryl, more preferably optionally substituted phenyl or optionally substituted heteroaryl, and even more preferably optionally substituted indolyl, optionally substituted benzofuranyl or optionally substituted benzoxazolyl.
R3 is independently in each occurrence preferably optionally substituted aryl or optionally substituted heteroaryl, more preferably optionally substituted phenyl or optionally substituted indolyl or pyridyl, and even more preferably optionally substituted phenyl.
R4 is xe2x80x94COOH or tetrazolyl, more preferably xe2x80x94COOH.
m, p and q are preferably 1 to 3; and more preferably 1.
n and r are preferably 0 to 3, and more preferably 0.
A is independently in each occurrence a single bond, xe2x80x94O(CH2)pxe2x80x94, xe2x80x94S(CH2)pxe2x80x94, xe2x80x94NRxe2x80x2(CH2)pxe2x80x94, xe2x80x94(CH2)pOxe2x80x94, xe2x80x94O(CH2)pOxe2x80x94, xe2x80x94(CH2)pO(CH2)pxe2x80x94, xe2x80x94(CH2)nCO(CH2)nxe2x80x94, xe2x80x94CONxe2x80x94, xe2x80x94NCOxe2x80x94; xe2x80x94(CH2)pxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94; more preferably a single bond, xe2x80x94(CH2)pxe2x80x94, xe2x80x94O(CH2)pxe2x80x94, xe2x80x94(CH2)pOxe2x80x94, or xe2x80x94(CH2)pO(CH2)pxe2x80x94, and even more preferably xe2x80x94O(CH2)pxe2x80x94, xe2x80x94(CH2)pOxe2x80x94 or a single bond.
B is independently in each occurrence xe2x80x94(CH2)qxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94 or xe2x80x94CH2Nxe2x80x94; more preferably xe2x80x94(CH2)qxe2x80x94, and even more preferably xe2x80x94CH2xe2x80x94.
Other preferred compounds of the present invention include the pharmaceutically acceptable salts of the compounds of the present invention wherein the pharmaceutically acceptable salts are formed from an alkali metal, or an amine; more preferably the salts are formed from sodium, potassium, lithium, t-butylamine or dicyclohexylamine.
Exemplary particularly preferred compounds include: 2-(biphenyl-4-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(4-phenethyloxy-benzyloxycarbonylamino)-3-phenyl-propionic acid; (R)-2-(2-phenyl-benzofuran-5-ylmethoxycarbonylamino)-3-phenyl propionic acid; (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid; (R)-2-(5-phenyl-benzofuran-3-ylmethoxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(2-Fluoro-phenoxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid; 2-(3-fluoro-4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(3-fluoro-phenoxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; 2-(biphenyl-4-methoxycarbonyl)amino-3-(3-indolyl)propionic acid; 3-(3-benzenesulfonylamino-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; 3-(3-benzenesulfonylamino-phenyl)-2-(4-phenoxymethyl-benzyloxycarbonylamino)-propionic acid; 3-(3-benzenesulfonylamino-phenyl)-2-(biphenyl-4-ylmethoxycarbonylamino)-propionic acid; (S)-2-phenyl-2-(5-phenyl-1H-indol-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(4-chloro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(3-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(4-methoxy-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-3-(4-fluoro-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(4-methyl-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-(2-benzyl-benzofuran-5-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-3-phenyl-2-(5-phenyl-benzoxazol-2-ylmethoxycarbonylamino) propionic acid; (R)-3-phenyl-2-(2-phenyl-benzoxazol-5-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(1H-indol-4-yl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; 2-[4-(1H-indol-4-ylmethoxy)-benzyloxycarbonylamino]-3-phenyl-propionic acid; 2-(4-benzyloxybenzylcarbonylamino)-3-phenyl-propionic acid; 2-[4-(1H-indol-5-ylmethoxy)-benzyloxycarbonylamino]-3-phenyl-propionic acid; (R)-2-(5-benzo[1,3]dioxol-5-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid (R)-2-[5-(3-cyano-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-3-phenyl-2-(5-phenyl-2,3-dihydro-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-3-(4-fluoro-phenyl)-2-(5-pyridin-3-yl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[2-(4-fluoro-phenyl)-benzoxazol-5-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(3-cyano-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-[5-(3,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(2-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(2,3-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-3-(4-fluoro-phenyl)-2-[5-(2-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-2-[5-(2-chloro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-(5-benzo[1,3]dioxol-5-yl-benzofuran-2-ylmethoxycarbonylamino)-3-(4-fluoro-phenyl)-propionic acid; (R)-3-(4-chloro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-2-(5-benzo[1,3]dioxol-4-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid; (R)-2-[2-(3-cyano-phenyl)-benzoxazol-5-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-3-(4-bromo-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-3-(4-chloro-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-3-(3-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; (R)-3-(3-fluoro-phenyl)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(2,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(3,4-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[5-(2,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-[5-(3,4-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-2-[5-(3,5-difluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-3-(4-fluoro-phenyl)-propionic acid; (R)-3-phenyl-2-(2-phenyl-quinolin-6-ylmethoxycarbonylamino)-propionic acid; (R)-2-[5-(1H-indol-5-yl)-benzofuran-2-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[2-(1H-indol-4-yl)-benzoxazol-5-ylmethoxycarbonylamino]-3-phenyl-propionic acid; (R)-2-[2-(3,5-difluoro-phenyl)-benzoxazol-5-ylmethoxycarbonylamino]-3-phenyl-propionic acid; 2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-pyridin-4-yl-propionic acid; and 2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-pyridin-3-yl-propionic acid, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
Compounds of the present invention may be made by the methods depicted in the illustrative synthetic reaction schemes shown and described below.
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis; Wiley and Sons: New York, 1991, Volumes 1-15; Rodd""s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley and Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein preferably take place at atmospheric pressure over a temperature range from about xe2x88x9278xc2x0 C. to about 150xc2x0 C., more preferably from about 0xc2x0 C. to about 125xc2x0 C.
In general, the compounds of Formula I can be prepared by the process of the following Reaction Schemes. 
Alternatively, compound 17 can be synthesized as shown in the following scheme: 
Generally as set forth in reaction Schemes 1, 2, 3, and 4, the preparation of alcohols of formulae 4, 11, 17, and 22 can be effected with 2-isocyanato-3-phenyl-propionate 5 (prepared according to the method described by Nowick et al, J. Org. Chem. 1996, 61, 3929) in the presence of a base for example triethylamine or 4-dimethylaminopyridine (DMAP). Hydrolysis of the respective resulting esters of formulae 6, 12, 18, and 23 can be effected with an alkali hydroxide such as sodium, lithium or potassium in a lower alkanol solution to prepare acids of formulae 7, 13, 19 and 24 respectively.
Compounds of formulae 4 and 11 of Schemes 1 and 2 can be prepared by alkylation of phenols of formulae 2 and 9 with haloalkylbenzoic acid, preferably chloroalkylbenzoic acid or bromoalkylbenzoic acid, in the presence of an excess amount of a suitable base, for example potassium hydroxide, potassium carbonate, sodium carbonate, preferably potassium hydroxide in a suitable solvent preferably dimethyl sulfoxide (DMSO), and further reduction with, for example, lithium aluminum hydride or borohydride in a suitable inert ether solvent such as tetrahydrofuran (THF), diethylether or dimethoxyethane.
Compounds of formulae 17 and 22 of Schemes 3 and 4 can be prepared from a halobenzofuran carboxylate, preferably bromobenzofuran carboxylate 15 with benzeneboronic acid and thiopheneboronic acid respectively in the presence of a catalyst preferably tetrakis-triphenylphosphine-palladium and a base such as sodium carbonate or potassium carbonate, and further reduction of the acids with, for example, lithium aluminum hydride or borohydride in a suitable solvent such as THF, diethyl ether or 1,2-dimethoxyethane. Aryl halides coupling to boronic acids have been described in the chemical literature, for example Synth. Commun., 1981, 11, 513, and Chem. Rev., 1995, 95, 257.
Alternatively, compound 17 can be prepared from a certain 4-biphenol, that after iodination into the 3-iodo substituent following the procedure described in J. Org. Chem.,1990, 55, 5287, and followed by a condensation with the terminal acetylene of an acetylenic alcohol such as prop-2-yn-1-ol or but-3-yn-1-ol in the presence of bis-(triphenylphosphine)palladium (II) chloride, copper iodide and a base such as tetramethylguanidine in a suitable solvent such as DMF following the procedure in Tetrahedron Letters, 1997, 38, 2311.
Exemplary preparations of Schemes 1, 2, 3 and 4 are given in Examples 1, 2, 3, and 4 respectively. Alternate preparations of compound 17 can be found in Example 3. 
Generally as set forth in reaction Scheme 5, 3-iodo-4-hydrobenzoate of formula 26 can be prepared according to the procedure described in C. W. Holzapfel et al. Tetrahedron 1995, 51, 8555. An ester of formula 27 can be prepared according to the procedure of D. Francelli et al., Tetrahedron Letters, 1997, 38, 237 by condensation of the iodohydrobenzoate of formula 26 with phenylacetylene or phenylalkylacetylene in the presence of bis-(triphenylphosphine)-palladium(II)chloride in a suitable solvent. A propionic acid of formula 29 can be prepared by reduction of a methyl ester of formula 27 with lithium aluminum hydride or borohydride, followed by acylation with 2-isocyanato-3-phenyl-propionate 5, and hydrolysis according to the procedures in the aforementioned schemes.
Exemplary preparations of Scheme 5 are given in Example 5. 
Generally as set for in reaction Scheme 6, biphenyl-4-methyl formate of formula 31 wherein L is a leaving group, for example chloro, can be prepared when biphenylmethanol 30 is treated with phosgene in an inert chlorinated solvent such as chloroform or methylene chloride. Acylation of the choloroformate can be effected with phenylalanine ester in the presence of a base such as sodium or potassium bicarbonate in a suitable solvent, for example methylene chloride, and then hydrolyzed to prepare an acid of formula 33. Hydrolysis can be effected following the aforementioned procedures.
Exemplary preparation of Scheme 6 are given in Example 6. 
Generally the reaction Scheme 7 follows the same procedures as Scheme 6, but the acylation is effected substituting phenylalanine ester hydrochloride with optionally substituted tryptophan ester hydrochloride in a suitable solvent such as methylene chloride.
Exemplary preparations of Scheme 7 are given in Example 6. 
Generally as set forth in Scheme 8, a methyl ester of formula 37 can be prepared by reaction of a chloromethylbenzyl alcohol of formula 36 with the isocyanate of formula 5 following the procedures of the precedent schemes. Esters of formula 38 (R1=phenyl) and 39 (R1=indolyl) can be prepared by alkylation with p-fluorophenol or indolol respectively in the presence of a base such as sodium, potassium or cesium carbonate, preferably cesium carbonate in a suitable solvent such as DMSO or methylene chloride. Hydrolysis following the precedent procedures can be carried out in preparing the respective acids of formulas 40 (R1=phenyl) and 41 (R1=indolyl).
Exemplary preparations of Scheme 8 are given in Example 7. 
Generally as set forth in Scheme 9, 5-phenyl-1H-indole 42 can be prepared following the procedure described by Y. Yang et al, Heterocycles, 1992, 34, 1169, from indoleboronic acid in the presence of a catalyst such as tetrakis-(triphenylphosphine)-palladium and a base such as sodium or potassium carbonate in a suitable solvent such as dioxane. The phenylindolecarboxylic acid ester 44 can be prepared after protection of the amino group with a suitable protecting group as described herein, preferably t-butoxycarbonyl, deprotonation with a strong base such as t-butyllithium, carboxylation and removal of the nitrogen protective group. Removal of the nitrogen protective group can be effected by means as described herein. A detailed description of the techniques applicable to protective groups and their removal can be found in T. W. Greene, Protective Groups in Organic Synthesis, Wiley and Sons, New York, 1991. For example a method of deprotection when the protective group is N-t-butoxycarbonyl can be carried out with trifluoroacetic acid or hydrochloric acid in a suitable solvent or a mixture of suitable inert organic solvents. 2-(5-Phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid 47 can be prepared after reduction, acylation and hydrolysis of the compound of formula 44 following the procedures of the precedent schemes.
Exemplary preparations of Scheme 9 are given in Example 8. 
Generally as set forth in Scheme 10, 2-methyl-5-phenylbenzoxazole 48 can undergo a radical bromination in the presence of for example azodiisobutyronitrile (AIBN) or benzoyl peroxide, preferably AIBN, and N-bromosuccinimide in a suitable solvent such as carbon tetrachloride to yield a corresponding bromomethyl derivative of formula 49. Replacement of the bromide with an acetate can be effected with an acetate such as cesium acetate in an inert solvent such as dimethylformamide. Removal of the acetate in a compound of formula 50 can be effected with a base such as sodium or potassium carbonate preferably potassium carbonate in a suitable solvent such as methanol to yield an alcohol of formula 51. An allyl ester of formula 52 can be prepared by reaction with carbonyldiimidazole in a suitable solvent such as methylene chloride, and further addition of the tosic salt of phenylalanine allyl ester (prepared according to the procedure of Waldman and Kunz, Liebigs Ann. Chem., 1983, 1712) in the presence of a base such as triethylamine in a suitable solvent such as methylene chloride. An acid of formula 53 can be prepared by deprotection in ethanol in the presence of a suitable catalyst such as tris(triphenylphosphine)-rhodium chloride at approximately 80xc2x0 C.
Exemplary preparations of Scheme 10 are given in Example 9. 
Generally as set forth in Scheme 11, 2-benzylideneamino-4-methylphenol 54 can be prepared following the procedure described by A. W. Baker, J.Am.Chem.Soc., 1959, 81, 1524, from 2-amino-p-cresol and benzaldehyde in a suitable solvent such as methanol. 5-Methyl-2-phenylbenzoxazole 55 can be prepared following the procedure described by R. Varma et al., J. Heterocyclic Chem., 1998, 35, 1539 by cyclization of 2-benzylideneamino-4-methylphenol 54 with manganese (III) acetate dihydrate in a suitable inert solvent such as benzene or toluene, preferably toluene. Radical bromination of the methyl group can be effected by means described in Scheme 10 in the presence of azodiisobutyronitrile (AIBN) or benzoyl peroxide, preferably AIBN, and N-bromosuccinimide in a suitable solvent such as carbon tetrachloride to yield 5-bromomethyl-2-phenylbenzoxazole 56. Replacement of the bromide derivative of formula 56 can be effected with an acetate such as potassium or cesium acetate, preferably cesium acetate in an inert solvent such as dimethylformamide, followed by hydrolysis to yield the alcohol of formula 58. Acylation of the alcohol of general formula 58 with 2-isocyanato-3-phenyl-propionate 5, followed by hydrolysis according to the procedures in the aforementioned schemes can give (R)-2-(2-phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenyl propionic acid 60.
Exemplary preparations of Scheme 11 are given in Example 10. 
Generally as set forth in Scheme 12, (5-pyridin-3-yl-benzofuran-2-yl)-methanol 61 can be prepared following the procedure of Scheme 3 for compound 17 but replacing benzeneboronic acid with diethyl 3-pyridyl borane. Acylation with 4-nitrophenyl chloroformate in an halogenated solvent such as dichloromethane can give 5-pyridin-3-yl-benzofuran-2-ylmethyl p-nitrophenyl carbonate 62, which when treated with 2-amino-3-pyridin-4-yl-propionic acid methyl ester (method for the synthesis is described in the chemical literature, for example J. Org. Chem., 1958, 23, 575) and DMAP in a suitable inert solvent such as DMF, followed by hydrolysis can give 3-pyridin-4-yl-2-(5-pyridin-3-yl-benzofuran-2-ylmethoxycarbonylamino)-propionic acid 63.
Exemplary preparations of Scheme 12 are given in Example 11. 
Generally as set forth in Scheme 13, allyl bromide can react with 4-phenylphenol 64 to give the allyl ether 65 that under basic conditions can undergo Claisen rearrangement to prepare an allyl alcohol 66. Treatment with peracetic acid can effect cyclization to the 2,3-dihydro-benzofuran-2-yl alcohol 67. Following the procedure of Schemes 1 to 5 treatment with 2-isocyanato-3-phenyl-propionate 5, and hydrolysis can give the acid of formula 68.
Exemplary preparations of Scheme 13 are given in Example 12. 
Generally as set forth in Scheme 14, 4-vinylbenzoic acid 69 can be esterified following the procedure in Liebigs Ann. Chem., 1988, 559-563, in methanol with thionylchloride. The vinyl benzoate 70 can be hydroborated with 9-BBN or BH3, preferably 9-BBN, followed by oxidation with an alkaline peroxide in an inert solvent, preferably tetrahydrofuran, to yield the alcohol of Formula 71. Conversion into the phenyl ether 72 can be effected with addition of phenol in the presence of diethyl azodicarboxylate and triphenyl phosphine, in an inert solvent such as tetrahydrofuran, following a procedure in Synthesis, 1981,1, or in J.Chem.Soc.Perkin Trans. 1981, 1, 2328. Reduction of the benzoate of formula 72, condensation with an isocyanate of Formula 5, and hydrolysis as in the previous schemes can give the compound of Formula 73.
General Utility
The IP receptor antagonists such as those described in this invention preferably possess anti-inflammatory and/or analgesic properties in vivo. Accordingly, preferred compounds are useful as anti-inflammatory and/or analgesic agents in mammals, especially humans. They find utility in pain conditions from a wide variety of causes, including but not limited to, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders such as irritable bowel syndrome.
Preferred compounds also find utility in inflammatory conditions from a variety of causes, including but not limited to, bacterial, fungal or viral infections, rheumatoid arthritis, osteoarthritis, surgery, bladder infection or idiopathic bladder inflammation, over-use, old age, or nutritional deficiencies, prostatitis, and conjunctivitis.
Preferred compounds also find utility in bladder disorders associated with bladder outlet obstruction and urinary incontinence conditions such as bladder outlet obstruction, urinary incontinence, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiophatic bladder hypersensitivity.
Preferred compounds also find utility in the treatment of hypotensive vascular diseases such as hypotension associated with septic shock.
In addition, preferred compounds also find utility in the treatment of respiratory diseases such as allergies and asthma.
These and other therapeutic uses are described, for example, in Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, 1996, Chapter 26:601-616; and Coleman, R. A., Pharmacological Reviews, 1994, 46, 205-229.
Testing
The binding affinity of these compounds to the intended target may be measured with the in vitro Human Platelet IP receptor binding Assay as described in more detail in Example 23. The anti-inflammatory/analgesic activity of the compounds of this invention may be assayed by in vivo assays such as the Rat Carrageenan Paw Assay, the Rat Complete Freund""s Adjuvant-induced Assay, and the Carbaprostacyclin Induced Writhing Test as described in more detail in Examples 24, 25, and 29 respectively. The inhibition of bladder contractions of this invention may be assayed by in vivo assays such as Inhibition of Bladder Contractions Induced by Isovolumetric Bladder Distension in Rats and Inhibition of Volume-Induced Contractions in Rats, as described in more detail in Examples 26 and 27 respectively. Activity in the inhibition of the septic shock may be assayed by in vivo assays such as the Rat Reversal of Endotoxin-Induced Hypotension Assay, as described in more detail in Example 28.
Administration and Pharmaceutical Composition
The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. In general, compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
The compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in a transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in Examples 16-22.